Worldwide, hepatocellular carcinoma (HCC) is the third most common cause of cancer deaths in men and the seventh most common in women. About 80% of the cases of HCC are associated with chronic infection with hepatitis B virus (HBV), but chronic carriers of HBV differ widely in their risk of HCC. Prospective studies of 60,984 men in Haimen City, China and 19,469 men in Senegal, west Africa, undertaken during the current funding period, revealed a 14-fold greater death rate from HCC among the Haimen than the Senegalese cohort. The age-adjusted prevalence of chronic HBV infection is about 20% in both cohorts. Exposure to aflatoxin, a postulated major risk factor for HCC, does not distinguish these two populations; Senegalese men were universally and heavily exposed. The prevalence of viremia (HBV DNA in serum) among HBV carriers throughout adult life is much higher among the Chinese than the Senegalese population and may be related to the mechanism by which chronic HV infection induces HCC. The mechanism, however, is still unknown. Therefore, the purpose of this program project is to understand the inter- relationships of HBV and other viral infections, environmental factors, genetic events and gene-environment interactions to the etiology and pathogenesis of (HCC). The Specific Aims are: 1) To compare variations in viral, genetic, and environmental factors associated with development of HCC to variations in risk of HCC observed in 3 cohort studies in China, Senegal, and Philadelphia. 2) To understand the cellular and molecular changes in the liver induced by chronic molecular genetic changes in tumor cells associated with HCC. 4) To identify genetic factors and gene- environment interactions associated with susceptibility to HCC. A multi- disciplinary team of scientists from China, Senegal, and the Fox Chase Cancer Center will address these Aims in three Projects (Molecular Epidemiology of HBV and HCC in Three Populations, Genetic Epidemiology of HCC, and Pathobiology of Acute and Chronic Hepadnavirus Infections) supported by three Core facilities (Population Resources, Laboratory Services, Administration). The ultimate goal of this research is to develop strategies for reducing the global burden of HCC.